Freeze-drying is a method of gentle desiccation of delicate products, e.g. pharmaceuticals, which cannot tolerate drying at elevated temperatures. The product to be dried is aliquoted into containers (e.g. partially glass vials sealed with a stopper), which are placed on a cooled, temperature controlled shelf within the freeze dryer. The shelf temperature is reduced and the product is cooled to a uniform, defined temperature. After complete freezing, the pressure in the dryer is lowered to a defined pressure to initiate primary drying. During the primary drying, water vapor is progressively removed from the frozen mass by sublimation whilst the shelf temperature and chamber vacuum are controlled at an exactly defined level. Secondary drying is initiated by increasing the shelf temperature and reducing the chamber pressure further so that water adsorbed to the product structure can be removed until the residual water content decreases to the desired level. The containers can be sealed in situ, under a protective atmosphere if required.
While freeze-drying is a known technique per se, it still represents a challenge because even when implemented by a skilled staff great care is necessary to control the process without damaging the product to be freeze-dried.
Another major issue is that a defined residual moisture must be reached in the final product before stopping the freeze-drying process. If the residual moisture is too high it may affect the stability of the active ingredient and thus the pharmaceutical grade of the product. It must hence be ascertained that the residual moisture has reached the defined level before stopping the freeze-drying process.
However, precisely determining at which point the freeze-drying process must be stopped would mean measuring the residual moisture in each vial during the freeze-drying process before taking the decision of stopping the freeze-drying. This is almost impossible to do in practice with a large number of vials as it is generally the case in the pharmaceutical field, since it would require stopping the freeze-drying process several times and taking the vials out of the freeze-drying device for measuring the residual moisture in each vial. This would be on the one hand very time consuming and on the other hand it would adversely affect the freeze-drying process, especially when the freeze-drying process must be conducted in sterile conditions.
Currently, the solution adopted by the pharmaceutical industry is to include a safety period by prolonging the period of freeze-drying past the empirically determined drying time in order to ascertain that the residual moisture is under a defined level.
There is hence a need for an apparatus for monitoring the residual moisture in the products subjected to a freeze-drying process for, inter alia, determining the end of the freeze-drying process and save the costs and inconvenience associated with the safety period.
The prior art already described means to monitor or control a freeze-drying process by monitoring one or several physical parameters as described hereinafter.
One of these parameters is the product temperature. The product temperature changes during the primary drying process and converges towards the shelf temperature. At the end of the sublimation phase (primary drying), little water (or solvent) is left and consequently the amount of chill by evaporation is reduced. By monitoring the product temperature with sensors, the end of the sublimation phase can be roughly estimated and correlated to the residual moisture in the products. However, the temperature probes influence the freeze-drying process. This can result in an early change to the secondary drying (desorption phase) which can destroy the structure of the dried product (Meltback). As this test is destructive, only a few samples out of a large population (product) can be tested and one cannot ascertain that the whole population of samples (product) is sufficiently dry.
Another parameter is the pressure. On availability of a pirani-type and a capacitance-type vacuum gauge, a comparative pressure measurement can give hints towards the composition of the process gas in the chamber. In this case the dependence of the pirani-signal on the composition of the gas (in particular on the water vapor content) and the independence of the capacitance signal (representing the absolute pressure) upon the water vapor content results in an “apparent” pressure difference. This difference is reduced with the progression of the drying process and subsequently of the changing gas composition inside the chamber. However, this measurement is not accurate and can only give a hint towards the status of the drying process.
Another way of using the measurement of pressure is the pressure rise test. During the pressure rise test, the freeze-drying chamber is completely sealed against mass transfer. The pressure difference is recorded over a defined period of time (usually several minutes). The time dependent pressure difference is correlated towards a certain drying status of the material inside the chamber. This test is mainly applied at the end of the secondary drying, to confirm, that the drying status of the material inside the chamber is within the specified level. Nevertheless, if a large number of items is dried, the contribution of a single item to the total pressure rise result is very small. For that reason, the test can not identify single items or small groups of items that are not dried properly.
Still another parameter is the water vapor partial pressure inside the process gas of a freeze-drying chamber. In this case an aluminum oxide dew point sensor can be used. The Al2O3 capacitive dew point sensor can measure directly the water vapor partial pressure inside the process gas of a freeze-drying chamber. This technique is very sensitive (e.g. −90° C. dewpoint) and can monitor the changes of the process gas during the whole process. This can help to identify the end of the primary drying phase. Furthermore, the measured value at the end of the secondary drying can also be correlated to a certain drying state of the product. The dew point sensors however suffer a major drawback since they can not tolerate sterilizing conditions (e.g. water steam, 121° C. 15 min), which are a requirement for drying e.g. pharmaceuticals.
Yet another parameter is the measure of the weight of the product. In this case, balances are applied in some areas to detect weight loss of the material to be dried. In the case of pharmaceutical applications, the vials are weighed over time to determine weight loss due to the evaporating water. This method is not applicable during commercial production of clinical material, as the balances are not sterilizable. Furthermore, it is known that items directly adjacent to the balance do not dry representatively. This fact can lead to misjudgments concerning the drying state of the other items in one batch. A further disadvantage is that only a few samples out of a large population (product) can be tested.
The measurement of the water vapor has been described by Winter et. al. and U.S. Pat. No. 6,848,196 B2 as a measurable parameter for monitoring the freeze-drying process. This method involves the use of a near infrared spectrometer (NIR: Near Infrared) coupled to a light fiber to measure the residual water content of a lyophilized pharmaceutical product in situ during the process. However, the NIR-irradiation can only penetrate a few millimeters into the dried material. Therefore a representative measurement of the entire vial is not possible. It is known that any material being adjacent to a vial can influence the drying behavior of the content of the container. Thus, the vial will not dry representatively. A further disadvantage is that only a few samples out of a large population (product) can be tested and hence a global monitoring, of the entire population cannot be achieved.
This short review of the prior art shows that the means currently available for the monitoring of a freeze-drying process are not completely satisfying and still presents many disadvantages.
The objective of the invention is to overcome the inconvenience associated with the prior art and to provide an apparatus and a method which allow the monitoring of a freeze-drying process in accordance with the requirements of the pharmaceutical field.